65) CLINGEN
9.8 E-5 MAF 5
0.095 2.2E-3
3
MAF 3
4 4
set OI set2
） 2
HPP EvC set3 ）
set
2 ATD set2 set4 ）
2
OI 3.5KJPNv2 PLOD2
p.Gln553Arg p.Asn457Asp ExAC “
p < 0.001 PLOD2 0.03551
4 set2 1/3,074
1/22,000 2
100
InterVar
p.Asn457Asp
2 （
（
ExAC HGVD
2
HPP
p.Ala177Thr p.Ala177Thr set4 ）
set3 HPP 1/56,287 set4
1/2,102 OI
HPP
30)
set3
1/56,287
ATD 3.5KJPNv2
22
1/338,189 set2 1/193,828 set4 1/64,000
InterVar VUS
IFT80
ATD （
22, 23) （
ATD NGS
55)
EvC
1/450,000
1/278,790 EvC
78) Hardy Weinberg
ClinVar HGMD
ACMG-AMP InterVar
pathogenic likely pathogenic
set2 ） OI
ATD 4
ExAC “
6
OI ATD
ClinVar HGMD
）
75, 76, 77) ClinVar HGMD
pathogenic
likely pathogenic
5 ClinVar pathogenic HGMD DM
InterVar VUS EvC
p.Arg950Trp HPP p.Arg136His p.Phe327Leu c.1559delT
4 ACMG-AMP
” “
InterVar 18
10
InterVar de novo
VUS
） pathogenic likely pathogenic
ALPL
p.Phe327Leu c.1559delT 72, 73)
p.Phe327Leu c.1559delT 3.5KJPNv2
ExAC “
p < 0.001 c.571G>A c.1133A>T
c.571G>A “ HPP 50%
c.1133A>T HPP
79) c.571G>A c.1133A>T 3.5KJPNv2
ClinVar
HGMD 3.5KJPNv2
”
3.5KJPNv2
3,552 ”
3.5KJPNv2
3.5KJPNv2
OI PPIB FKBP10 WNT1 CREB3L1 SP7 ATD
IFT80
3,552
3,552 ”
ACMG-AMP InterVar
10
de novo in vitro in vivo
･ 3.5KJPNv2
Insertion Deletion
3.5KJPNv2
X
OI HPP
・ 3.5KJPNv2
）
（
OI HPP EvC ATD （
HPP
。
「
“”
. 〜
OI Osteogenesis imperfecta
ATD Asphyxiating thoracic dysplasia
EvC Ellis-van Creveld dysplasia
HPP Hypophosphatasia
NGS Next generation sequence
WES Whole-exome sequencing
SNV single nucleotide variant
MAF Minor allele frequency
HGMD Human Gene Mutation Database
P pathogenic
LP likely pathogenic
VUS variant of uncertain significant
LB likely benign
B benign
HGVD Human Genetic Variation Database
1) Krakow, D., Rimoin, D.L. (2010) The skeletal dysplasias. Genet Med, 12,
327-341.
2) Geister, K.A., Camper, S.A. (2015) Advances in Skeletal Dysplasia
Genetics. Annu Rev Genomics Hum Genet, 16, 199-227.
3) Forlino, A., Marini, J.C. (2016) Osteogenesis imperfecta. The Lancet, 387,
1657-1671.
4) Sobacchi, C., Schulz, A., Coxon, F.P., et al. (2013) Osteopetrosis: genetics,
treatment and new insights into osteoclast function. Nat Rev Endocrinol,
9, 522-536.
5) Sillence, D.O., Rimoin, D.L., Danks, D.M. (1979) Clinical variability in
osteogenesis imperfecta-variable expressivity or genetic heterogeneity.
Birth Defects Orig Artic Ser, 15, 113-129.
6) Forlino, A., Cabral, W.A., Barnes, A.M., et al. (2011) New perspectives on
osteogenesis imperfecta. Nat Rev Endocrinol, 7, 540-557.
7) Marini, J.C., Blissett, A.R. (2013) New genes in bone development: what's
new in osteogenesis imperfecta. J Clin Endocrinol Metab, 98, 3095-3103.
8) Marini, J.C., Forlino, A., Cabral, W.A., et al. (2007) Consortium for
osteogenesis imperfecta mutations in the helical domain of type I collagen:
regions rich in lethal mutations align with collagen binding sites for
integrins and proteoglycans. Hum Mutat, 28, 209-221.
9) Pollitt, R.C., Saraff, V., Dalton, A., et al. (2016) Phenotypic variability in
patients with osteogenesis imperfecta caused by BMP1 mutations. Am J
Med Genet A, 170, 3150-3156.
10) Vranka, J.A., Sakai, L.Y., Bachinger, H.P. (2004) Prolyl 3-hydroxylase 1,
enzyme characterization and identification of a novel family of enzymes. J
Biol Chem, 279, 23615-23621.
11) Davis, E.C., Broekelmann, T.J., Ozawa, Y., et al. (1998) Identification of
tropoelastin as a ligand for the 65-kD FK506-binding protein, FKBP65, in
the secretory pathway. J Cell Biol, 140, 295-303.
12) Koide, T., Asada, S., Takahara, Y., et al. (2006) Specific recognition of the
collagen triple helix by chaperone HSP47: minimal structural requirement
and spatial molecular orientation. J Biol Chem, 281, 3432-3438.
13) Quan, G.M., Ojaimi, J., Li, Y., et al. (2005) Localization of pigment
epithelium-derived factor in growing mouse bone. Calcif Tissue Int, 76,
146-153.
14) Garbes, L., Kim, K., Riess, A., et al. (2015) Mutations in SEC24D,
encoding a component of the COPII machinery, cause a syndromic form
of osteogenesis imperfecta. Am J Hum Genet, 96, 432-439.
15) Baron, R., Kneissel, M. (2013) WNT signaling in bone homeostasis and
disease: from human mutations to treatments. Nat Med, 19, 179-192.
16) Murakami, T., Saito, A., Hino, S., et al. (2009) Signalling mediated by the
endoplasmic reticulum stress transducer OASIS is involved in bone
formation. Nat Cell Biol, 11, 1205-1211.
17) Lapunzina, P., Aglan, M., Temtamy, S., et al. (2010) Identification of a
frameshift mutation in Osterix in a patient with recessive osteogenesis
imperfecta. Am J Hum Genet, 87, 110-114.
18) Bonafe, L., Cormier-Daire, V., Hall, C., et al. (2015) Nosology and
classification of genetic skeletal disorders: 2015 revision. Am J Med Genet
A, 167A, 2869-2892.
19) Zhang, W., Taylor, S.P., Ennis, H.A., et al. (2018) Expanding the genetic
architecture and phenotypic spectrum in the skeletal ciliopathies. Hum
Mutat, 39, 152-166.
20) Jeune, M., Beraud, C., Carron, R. (1955) [Asphyxiating thoracic dystrophy
with familial characteristics]. Archives francaises de pediatrie, 12, 886-891.
21) de Vries, J., Yntema, J.L., van Die, C.E., et al. (2010) Jeune syndrome:
description of 13 cases and a proposal for follow-up protocol. Eur J Pediatr,
169, 77-88.
22) Oberklaid, F., Danks, D.M., Mayne, V., et al. (1977) Asphyxiating thoracic
dysplasia. Clinical, radiological, and pathological information on 10
patients. Arch Dis Child, 52, 758-765.
23) Baujat, G., Huber, C., El Hokayem, J., et al. (2013) Asphyxiating thoracic
dysplasia: clinical and molecular review of 39 families. J Med Genet, 50,
91-98.
24) Ruiz-Perez, V.L., Ide, S.E., Strom, T.M., et al. (2000) Mutations in a new
gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis.
Nat Genet, 24, 283-286.
25) Galdzicka, M., Patnala, S., Hirshman, M.G., et al. (2002) A new gene,
EVC2, is mutated in Ellis-van Creveld syndrome. Mol Genet Metab, 77,
291-295.
26) FRASER, D. (1957) Hypophosphatasia. Am J Med, 22, 730-746.
27) Weiss, M.J., Ray, K., Fallon, M.D., et al. (1989) Analysis of
liver/bone/kidney alkaline phosphatase mRNA, DNA, and enzymatic
activity in cultured skin fibroblasts from 14 unrelated patients with severe
hypophosphatasia. Am J Hum Genet, 44, 686-694.
28) Bowden, S.A., Foster, B.L. (2018) Profile of asfotase alfa in the treatment
of hypophosphatasia: design, development, and place in therapy. Drug
Des Devel Ther, 12, 3147-3161.
29) Ozono, K., Yamagata, M., Michigami, T., et al. (1996) Identification of novel
missense mutations (Phe310Leu and Gly439Arg) in a neonatal case of
hypophosphatasia. J Clin Endocrinol Metab, 81, 4458-4461.
30) Mornet, E. (2017) Genetics of hypophosphatasia. Arch Pediatr, 24,
5S51-55S56.
31) Whyte, M.P., Greenberg, C.R., Salman, N.J., et al. (2012)
Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med,
366, 904-913.
32) Orioli, I.M., Castilla, E.E., Barbosa-Neto, J.G. (1986) The birth prevalence
rates for the skeletal dysplasias. J Med Genet, 23, 328-332.
33) Camera, G., Mastroiacovo, P. (1982) Birth prevalence of skeletal
dysplasias in the Italian Multicentric Monitoring System for Birth Defects.
Prog Clin Biol Res, 104, 441-449.
34) Lindahl, K., Astrom, E., Rubin, C.J., et al. (2015) Genetic epidemiology,
prevalence, and genotype-phenotype correlations in the Swedish
population with osteogenesis imperfecta. Eur J Hum Genet, 23,
1042-1050.
35) D'Asdia, M.C., Torrente, I., Consoli, F., et al. (2013) Novel and recurrent
EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers
acrofacial dyostosis. Eur J Med Genet, 56, 80-87.
36) Phillips, J.D., van Aalst, J.A. (2008) Jeune's syndrome (asphyxiating
thoracic dystrophy): congenital and acquired. Semin Pediatr Surg, 17,
167-172.
37) Mornet, E., Yvard, A., Taillandier, A., et al. (2011) A molecular-based
estimation of the prevalence of hypophosphatasia in the European
population. Ann Hum Genet, 75, 439-445.
38) Greenberg, C.R., Taylor, C.L., Haworth, J.C., et al. (1993) A homoallelic
Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of
hypophosphatasia in Canadian mennonites. Genomics, 17, 215-217.
39) , , . (2009)
. , 45,
1005-1007.
40) Watanabe, A., Yamamasu, S., Shinagawa, T., et al. (2007) Prenatal
genetic diagnosis of severe perinatal (lethal) hypophosphatasia. J Nippon
Med Sch, 74, 65-69.
41) Sugano, H., Matsumoto, T., Miyake, K., et al. (2012) Successful gene
therapy in utero for lethal murine hypophosphatasia. Hum Gene Ther, 23,
399-406.
42) Okazaki, Y., Kitajima, H., Mochizuki, N., et al. (2016) Lethal
hypophosphatasia successfully treated with enzyme replacement from
day 1 after birth. Eur J Pediatr, 175, 433-437.
43) Bae, J.S., Kim, N.K., Lee, C., et al. (2016) Comprehensive genetic
exploration of skeletal dysplasia using targeted exome sequencing. Genet
Med, 18, 563-569.
44) Taillandier, A., Domingues, C., De Cazanove, C., et al. (2015) Molecular
diagnosis of hypophosphatasia and differential diagnosis by targeted Next
Generation Sequencing. Mol Genet Metab, 116, 215-220.
45) Cossu, C., Incani, F., Serra, M.L., et al. (2016) New mutations in DYNC2H1
and WDR60 genes revealed by whole-exome sequencing in two unrelated
Sardinian families with Jeune asphyxiating thoracic dystrophy. Clin Chim
Acta, 455, 172-180.
46) Krakow, D. (2015) Skeletal dysplasias. Clin Perinatol, 42, 301-319, viii.
47) Kato, H., Kitano, T., Iba, K. (2016) Surveillance Registry for Bone
Dysplasias of Japanese Orthopedic Association. J. Jpn. Orthop. Assoc.
48) Becker, J., Semler, O., Gilissen, C., et al. (2011) Exome sequencing
identifies truncating mutations in human SERPINF1 in
autosomal-recessive osteogenesis imperfecta. Am J Hum Genet, 88, 362-371.
49) Velasco, H.M., Morales, J.L. (2017) Novel mutation of FKBP10 in a
pediatric patient with osteogenesis imperfecta type XI identified by clinical
exome sequencing. In: Appl Clin Genet, New Zealand, pp. 75-83.
50) Tadaka, S., Katsuoka, F., Ueki, M., et al. (2019) 3.5KJPNv2: an allele
frequency panel of 3552 Japanese individuals including the X
chromosome. Hum Genome Var, 6, 28.
51) Kuriyama, S., Yaegashi, N., Nagami, F., et al. (2016) The Tohoku Medical
Megabank Project: Design and Mission. J Epidemiol, 26, 493-511.
52) Yasuda, J., Katsuoka, F., Danjoh, I., et al. (2018) Regional genetic
differences among Japanese populations and performance of genotype
imputation using whole-genome reference panel of the Tohoku Medical
Megabank Project. BMC Genomics, 19, 551.
53) Okada, Y., Momozawa, Y., Sakaue, S., et al. (2018) Deep whole-genome
sequencing reveals recent selection signatures linked to evolution and
disease risk of Japanese. Nat Commun, 9, 1631.
54) Auton, A., Brooks, L.D., Durbin, R.M., et al. (2015) A global reference for
human genetic variation. Nature, 526, 68-74.
55) Shaheen, R., Schmidts, M., Faqeih, E., et al. (2015) A founder CEP120
mutation in Jeune asphyxiating thoracic dystrophy expands the role of
centriolar proteins in skeletal ciliopathies. Hum Mol Genet, 24, 1410-1419.
56) Whyte, M.P., Rockman-Greenberg, C., Ozono, K., et al. (2016) Asfotase
Alfa Treatment Improves Survival for Perinatal and Infantile
Hypophosphatasia. J Clin Endocrinol Metab, 101, 334-342.
57) Kitaoka, T., Tajima, T., Nagasaki, K., et al. (2017) Safety and efficacy of
treatment with asfotase alfa in patients with hypophosphatasia: Results
from a Japanese clinical trial. Clin Endocrinol (Oxf), 87, 10-19.
58) Pauli, R.M., Modaff, P., Sipes, S.L., et al. (1999) Mild hypophosphatasia
mimicking severe osteogenesis imperfecta in utero: bent but not broken.
Am J Med Genet, 86, 434-438.
59) Yamaguchi-Kabata, Y., Yasuda, J., Uruno, A., et al. (2019) Estimating
carrier frequencies of newborn screening disorders using a whole-genome
reference panel of 3552 Japanese individuals. Hum Genet, 138, 389-409.
60) Wang, K., Li, M., Hakonarson, H. (2010) ANNOVAR: functional annotation
of genetic variants from high-throughput sequencing data. Nucleic Acids
Res, 38, e164.
61) Li, Q., Wang, K. (2017) InterVar: Clinical Interpretation of Genetic Variants
by the 2015 ACMG-AMP Guidelines. Am J Hum Genet, 100, 267-280.
62) Cooper, D.N., Ball, E.V., Krawczak, M. (1998) The human gene mutation
database. Nucleic Acids Res, 26, 285-287.
63) Stenson, P.D., Ball, E.V., Mort, M., et al. (2003) Human Gene Mutation
Database (HGMD): 2003 update. Hum Mutat, 21, 577-581.
64) Richards, S., Aziz, N., Bale, S., et al. (2015) Standards and guidelines for
the interpretation of sequence variants: a joint consensus
recommendation of the American College of Medical Genetics and
Genomics and the Association for Molecular Pathology. Genet Med, 17,
405-424.
65) Landrum, M.J., Lee, J.M., Benson, M., et al. (2016) ClinVar: public archive
of interpretations of clinically relevant variants. Nucleic Acids Res, 44,
D862-868.
66) Ren, Y., You, Y.Q., Zhou, H.H., et al. (2017) [Clinical analysis of 21 cases
with short fetal femur in the third trimester]. Zhonghua Fu Chan Ke Za Zhi,
52, 86-92.
67) Ruiz-Perez, V.L., Tompson, S.W., Blair, H.J., et al. (2003) Mutations in two
nonhomologous genes in a head-to-head configuration cause Ellis-van
Creveld syndrome. Am J Hum Genet, 72, 728-732.
68) Zhang, Z., Bao, K., He, J.W., et al. (2012) Identification of one novel
mutation in the EVC2 gene in a Chinese family with Ellis-van Creveld
syndrome. Gene, 511, 380-382.
69) Okamoto, T., Nagaya, K., Kawata, Y., et al. (2015) Novel compound
heterozygous mutations in DYNC2H1 in a patient with severe short-rib
polydactyly syndrome type III phenotype. Congenit Anom (Kyoto), 55,
155-157.
70) Perrault, I., Saunier, S., Hanein, S., et al. (2012) Mainzer-Saldino
syndrome is a ciliopathy caused by IFT140 mutations. Am J Hum Genet,
90, 864-870.
71) Taketani, T., Onigata, K., Kobayashi, H., et al. (2014) Clinical and genetic
aspects of hypophosphatasia in Japanese patients. Arch Dis Child, 99,
211-215.
72) Michigami, T., Uchihashi, T., Suzuki, A., et al. (2005) Common mutations
F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene
are related to distinct phenotypes in Japanese patients with
hypophosphatasia. Eur J Pediatr, 164, 277-282.
73) Watanabe, A., Karasugi, T., Sawai, H., et al. (2011) Prevalence of
c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal)
form of hypophosphatasia in Japanese and effects of the mutation on
heterozygous carriers. J Hum Genet, 56, 166-168.
74) Ozono, K., Michigami, T. (2011) Hypophosphatasia now draws more
attention of both clinicians and researchers: a commentary on Prevalence
of c. 1559delT in ALPL, a common mutation resulting in the perinatal
(lethal) form of hypophosphatasias in Japanese and effects of the mutation
on heterozygous carriers. J Hum Genet, 56, 174-176.
75) Dorschner, M.O., Amendola, L.M., Turner, E.H., et al. (2013) Actionable,
pathogenic incidental findings in 1,000 participants' exomes. Am J Hum
Genet, 93, 631-640.
76) MacArthur, D.G., Manolio, T.A., Dimmock, D.P., et al. (2014) Guidelines for
investigating causality of sequence variants in human disease. Nature,
508, 469-476.
77) Shi, L., Guo, Y., Dong, C., et al. (2016) Long-read sequencing and de novo
assembly of a Chinese genome. Nat Commun, 7, 12065.
78) Tompson, S.W., Ruiz-Perez, V.L., Wright, M.J., et al. (2001) Ellis-van
Creveld syndrome resulting from segmental uniparental disomy of
chromosome 4. J Med Genet, 38, E18.
79) Mornet, E. (2008) Hypophosphatasia. Best Pract Res Clin Rheumatol, 22,
113-127.
1. 73 3.5KJPNv250)
）
73 3.5KJPNv2 82,817 InterVar
Pathogenic Benign ） MAF 3%
ClinVar P LP reported
) interpreted ） VUS ClinVar
clinvar” HGMD ”hgmd”
4 ） set1 4 ） 59)
3.5KJPNv2 73
P LP VUS LB B
P_reported
LP_reported P_interpreted LP_ interpreted
p_clinvar
lp_clinvar p_hgmd
Set1
P_reported LP_reported
Set2
Set1 + P_interpreted LP_ interpreted
Set3
Set2 + p_clinvar lp_clinvar
Set4
Set3 + p_hgmd
InterVar
LB B
3.5KJPNv2 < 3%
> 3% →VUS
VUS
HGMD ClinVar ( P or LP )
yes no yes no yes no
yes/DM no
P ; Pathogenic LP ; Likely pathogenic VUS ; Variants of Uncertain Significance LB ; Likely benign B ; Benign
DM ; Disease-causing Mutation
2.
OI HPP ATD EVC 39) 4
3
set1 set4 1
1.0.E-08 1.0.E-07 1.0.E-06 1.0.E-05 1.0.E-04 5.0.E-04
OI HPP ATD EvC
Set1 P LP ”reported”
Set2 Set1 ”interpreted“ P LP Set3 Set2 VUS ClinVer P/LP Set4 Set3 VUS HGMD DM
1. 4
OI EvC ATD HPP
142 5 26
1,919,09434) 650,00022) 7,700,00037)
(1/x) 13,515 60,00035) 130,000 296,154
20 1 7 7
448,06939) 448,069 448,069 448,069
(1/x) 22,403 448,069 64,010 64,010
OI 2010 1,919,094 OI 142
ATD 1965 650,000 ATD 5
HPP ” 2006 770,000 HPP 26
39) 1989 20
2007 1 20
434,019 1 14,050
2 30 73
. . 201647)
hOihP hOWhP e 525 8C HIMN
525
58 ##
4 89
-9 8 #
882 # #
847 # ##
98261 03 8
98260 # #
-# #
6 # ##
-9 4 ##
8
58 # #
688 #
4- # #
878 ag
# dST Rf
7LM IB H LDL D KA M
1N I CIL C M D KD E ML
- (
2 68 (
26- (
28 ( )((
2 - (
3 28 (
4 ( )
8 26 ( )
2 3 ( )
( )
6 8) ( ) ) (
10 7 ( ) (
9 7 ( )( )
60537 ( (( ( )
2 ( )) (
8 ( ) (
4 2 ( )
81 1 ( (
81 1 ( )
( eUTY G KC NKNOKNFN 5 ( (
) cY aTX LK C HKIDOALE NDAH C NLHANFAN 7 ( (
OFBGHDMYTX OFBGHDM N CMKID 96 (
66 ( )( ))
30 ) ( ( ( (
SR d
Y
chYTX
7PBKLKH NABBEAMFCKNFN
9NODKLDOMKNFN
LK C HKBKNOAH C NKNOKNFN
Y V o 2TL L OL P OG 484 ) )(
168 - ( )
168 1 ( ) (
0 HDNO H Ooig 0 HDNO H O OTCN ID - 1 4 ) ( ) )
0 (
0 ( ) (
a yd hro BN IDO IDHGB CTOLH OG PTLD 5 N PD QS 5 5 68 ( ( )
6 ( (
4 ( ( )))
) ((
5 6 ( ( )
8 H C p 8 34367 OT CN ID 8 H C 0 94 ( ) ((
558 (
558 ( ( )
PHDT -GSHDNoig PHDT -GSHDN OT CN ID 87 )
mt e x hro 7P OL CTH IDE DLGL TOD H CTOLH OG 7 50 74
q hro G OPN L GB CTOLH OG 4 ( ( () (
5 ( ) (
- - ( (
u p hro TOODEID P H CTOLH OG 2 81 (
s vo PDH OPD ED DOGO PTLD 7 4 ( ( () (
Xlno
0HHGO R NDRDHC hro
( DOAQMQ GOoig
5QB HGLGC OGO
CN DBP CDNI H CTOLH OG 0HHGO R NDRDHC
) t x cx hro
b q cx hro
TEERD 5DHB G N H QOD hro
DOAQMQ GO CTOLH OG
L CTH DLG IDP L TOD H CTOLH OG O 05
5DP L TOD H CTOLH OG
QEERD 5DHB G N H QOD CTOLH OG 5
( cg gWT md he 9 JD C FPC COBJ ECOH NJFB BS G F 99 0 ;10
FNE JD C FPC NE J NES 5;9 (
0 7 4 ( ) (
0 ( ( ( (
52 ( )) ( (
52 ) ( ) ( ( (
52 ( ( ((
0 ( ( )(
( (
Yd he IFJHCN ES C G BS G F
36-9SGCd he 9SGC BF C C
J FIJ eb J FIJ SIB JHC 8 ( ) (
) a lig he - ESRF NFID NEJ AFA BS G F - 0 6COIC